Background. Approximately one-third of hepatoblastoma (HB) patients
have associated congenital abnormalities, but familial recurrence is
rare, except in association with familial adenomatous polyposis (FAP).
This correlation may be missed if not actively sought, with implications
for long-term outcome and management.

Results. Three FAP families (2.65%) had an HB association. In one
case, undiagnosed FAP at the time of HB diagnosis was only detected 5
years later, when the mother presented with advanced colorectal
carcinoma. A chromosome 5 APC gene mutation (exon 15 codon 793 C [right
arrow] T) then identified. In a second case, a non-related boy presented
with a stage 4 multifocal HB with lung metastases. Genetic studies
identified an APC gene mutation (exon 6 codon 232 C [right arrow] T).
Further family investigation showed >20 related FAP patients. A third
HB-FAP association was identified in a known FAP family early in the
study, prior to the availability of genetic testing.

Conclusion. Although a rare association, a family history of FAP in
HB patients is an important 'hidden connection'. Germline
variation may be outside the usual FAP gene site. Identifying families
with unknown HB/FAP is important due to long-term management
implications and follow-up.

Hepatoblastoma (HB) is the most common primary liver cancer of
childhood, accounting for up to 1% of all paediatric malignancies,
particularly in the younger child. HB is associated with congenital
abnormalities in approximately one-third of patients, suggesting complex
genetic and/or epigenetic factors in its pathogenesis. (1,2)

Familial recurrence of HB is extremely rare outside of associated
adenomatous polyposis coli (APC) families, (8) and a causative
relationship between HB and interstitial deletions of 5q21.3-q23.3 (the
APC gene region) is well known. (9) Consequently, offspring of FAP
families have a 750-7 500 times higher risk of developing HB. (10,11)
Although 75-80% of FAP individuals have APC gene mutations, there is a
group with non-typical de novo genetic variation. (6) As a result, the
screening of HB patients for APC gene variation in cases of childhood HB
without a family FAP history remains an open discussion. It appears to
be important to identify these high-risk individuals and perform
long-term screening to improve their management.

We aimed to investigate HB-FAP gene associations and clinical
implications in a South African population.

Methods

Based on available clinical data of 2 known FAP families, a local
database of 113 FAP cases (1989-2010) was investigated for HB
associations. Data were analysed for details of clinical problem,
treatment, complications and management. Long-term morbidity and
functional outcome were analysed to identify management difficulties.

Results

HB was evident in the offspring of 3/113 known FAP cases (2.65%).

Case 1

A 2-year-old child re-presented after absconding half-way through a
course of chemotherapy (cisplatinum and doxorubicin (PLADO)) for a stage
4 HB. Lung metastases were excised and a right hemi-hepatectomy of a
calcified tumour was performed with removal of an additional localised
lesion in the left lobe of the liver (Fig. 1). He has survived into
adulthood (22 years) without further HB metastatic events. He presented
with rectal bleeding at 14 years of age and a pedunculated adenomatous
polyp was identified on colonoscopy and removed. He subsequently
developed multiple rectal and colonic polyps, for which a total
colectomy was performed. Recurrence of rectal polyps in his rectal stump
necessitated revision of the lower rectal stump and fashioning of a
pouch. Genetic studies identified an APC gene mutation (exon 6 codon 232
C [right arrow] T). Further investigation of family history revealed
relations to a large well-known FAP mixed-ancestry family with >20
affected patients.

Case 2

A mixed-ancestry male infant in a family without any FAP history
was diagnosed with HB in the left liver lobe at 15 months of age.
Following 4 courses of PLADO, he underwent a left hepatectomy with
successful outcome. Six years later, the boy's 34-year-old mother
was diagnosed with advanced colon carcinoma and liver metastases. At
surgery, multiple colonic polyps were also noted. The mother and
child's APC genes showed the same mutation (exon 15 codon 793 C
[right arrow] T). The patient developed multiple adenomatous polyps, and
was successfully treated 15 years later by total colectomy. Two other
family members with the same genetic mutation have since been identified
and followed up.

[FIGURE 1 OMITTED]

Case 3

A male infant, born to a known FAP family, was diagnosed and
successfully treated for HB early in the study, prior to the
availability of genetic testing. The patient never developed further
features of FAP and there was no familial recurrence.

Discussion

HB is a well-known embryonal tumour, with recognised genetic
associations to several known cancer predisposition syndromes including
FAP. Family histories are uncommon in these, with the exception of
familial FAP, (8) as shown in this study. The incidence of FAP in
association with HB, identified in 3/113 FAP families (2.65%), was lower
than a previous report of 8/93 (8.6%) HB families. (12)

There are several lessons from this study. Firstly, although the
genetic links between HB and FAP are well established, it is a reminder
to clinicians of this rare, possibly hidden link. Secondly, the clinical
identification of associated FAP in our first case benefitted the
patient and led to the identification of a whole family at high risk of
cancer. Thirdly, from the second case, a full history in patients with
HB should include a family history of FAP. A timely genetic analysis for
FAP in the child with HB would have benefitted the mother who developed
an unsuspected metastatic carcinoma colon 6 years later on the basis of
unsuspected FAP. Fourthly, predicting HB susceptibility on the basis of
the site of APC mutation has proven difficult, as no significant
correlation between the site of mutation detected in those with or
without HB has been demonstrated. (13) The nature of the HB-associated
APC mutations, however, appears variable, as shown in 2 families in this
study where the APC mutation sites lay outside the
loss-of-heterozygosity (LOH)-associated region for colorectal FAP (i.e.
codons 1 285-1 378), (12,14) in keeping with previous reports. (8,15)

From a molecular perspective, these genetic associations may be a
more important link than previously thought in understanding the
oncogenesis of liver tumours such as HB. Chromosomal variations occur
frequently in HB, having been reported in up to 88% of cases in a genome
profiling study. (16) The most likely candidate genes identified thus
far are CTNNB1 (catenin, beta-1-catenin) (17) and insulin-like growth
factor II (IGF2) tumour suppressor at locus 11p15. (18,19) In addition,
more than 85% of HBs show accumulation of [beta]-catenin which indicates
an activated Wingless-type (Wnt) pathway. (20) Beta-catenin mutations
that play a key role in liver development, regeneration and oncogenesis,
are found in 50-90% of HB tumours. (21) However, multiple other deletion
or point mutations and frequent gains in chromosomes 1q, 2 (or 2q), 8,
17q, and 20 have been described in HB, as well as losses in chromosomes
4q and 11q, and high-grade amplifications at 7q34, 14q11.2, and 11q22.2.
(4) The HB-related Beckwith-Wiedemann syndrome is also associated with
the dysregulation and LOH of imprinted genes at chromosome 11p15.5. (22)
This subgroup is of considerable interest due to the location of the
IGF2 and H19 genes within this region, (16) indicating complex
genetic/epigenetic associations of the imprinted 11p15 region in the
pathogenesis of HB and other related tumours. (23,24)

The link to FAP is important because of the high risk of developing
HB in families with germline APC gene abnormalities. This risk is 750-7
500 times higher than in the general population, (10,11) as well as the
risk of other tumours occurring in familial gene carriers. The question
as to whether specific APC gene mutations are more likely to be
associated with HB remains open. In both cases tested genetically in
this series, the APC gene mutation lay outside the usual FAP site on
chromosome 5 (viz. family 1, part of a 20-strong known FAP ancestry:
exon 6 codon 232 C [right arrow] T; family 2: exon 15 codon 793 C [right
arrow] T). The significance of this is unknown, but it suggests that
those associated with HB may relate to other sites on the gene.

Understanding the link between FAP and HB may, therefore, be of the
utmost importance to patient evaluation and follow-up. Screening for APC
gene mutations in infants with HB, although difficult, facilitates
genetic counselling and an estimation of risk, owing to an autosomal
dominant hereditary pattern. (11) We agree that the presence of HB-risk
APC mutations justifies HB screening in neonates born to gene carriers.
(12)